Arterial thrombosis is primarily responsible for acute myocardial infarction, unstable angina and thrombotic stroke while venous thrombosis is associated with pulmonary embolism and deep vein thrombosis. A dynamic balance exists between coagulation and fibrinolysis which are regulated by the enzymes thrombin and plasmin, respectively. Superimposed on this is the process of platelet aggregation and platelet adhesion to vessel walls. Inhibition of platelet aggregation is a means of treating thrombosis for reperfusion injury. The present invention focuses on new chemical compounds which demonstrate platelet aggregation inhibition.
The present invention provides novel pyrimidinylaminothiazole compounds which are useful as inhibitors to platelet aggregation and adhesion molecules and novel intermediate compounds for producing such inhibitor compounds. The compounds of the invention are useful for treating reperfusion thrombosis injury in patients.
Various thiazole derivatives have been identified which have biological activity. For example U.S. Patent No. 4,791,200 discloses compounds of the formula: ##STR2## wherein R is H, alkyl, aryl or substituted phenyl and Ra and Rb are H, alkyl, aryl or substituted phenyl. These compounds are disclosed as antisecretory agents.
Chem. Pharm. Bull. 39 651-657 (1991) discloses compounds of the formula: ##STR3## wherein diphenylimidazole and diphenyl thiazole derivatives are described as inhibitors of platelet aggregation via an arachidonic acid mechanism.
Singh, et al. Indian Journal Of Chemistry 1983, 22B, 37-42, disclose a series of compounds of the following formula: ##STR4## wherein R is independently selected from H, OH, Me and OMe and the compounds are described as antinflammatory agents.
Beyer, et al. Chem. Ber. 1962, 89, 893-901, disclose a series of compounds of the following formula: ##STR5## wherein Ra is selected from phenyl, methyl or hydrogen, Rb is selected from methyl or hydroxyl, Rc is selected from hydrogen, bromine or chlorine. These compounds were apparently synthesized for their synthetic challenge alone.
Although the disclosed compounds of Singh, et al. and Beyer, et al. have an pyrimidinylaminothiazole backbone, their method of synthesis and their biological activity do not disclose or suggest the compounds of the present invention.
It is therefore an object of the present invention to provide novel thiazole derivatives which are useful as platelet aggregation inhibitors and their methods of use. Additional objects and advantages of the invention will be set forth, in part, in the description which follows and in part will be obvious from this description, or may be learned by practice of the invention. The objects and advantages of the invention are realized and obtained by means of the methods, and the combinations particularly pointed out in the appended claims.